Subendocardial vulnerability may be due to transmural gradients of metabolism and/or blood flow during ischemia. The relative importance of metabolic gradients and the physical determinants of blood flow gradients will be investigated. The significance of metabolic gradients will be tested with an experimental model that provides uniform transmural perfusion under ischemic conditions. We have confirmed that retrograde bleeding after coronary occlusion results in a deeply ischemic region with effective transmural uniform depletion of blood flow. Regional lactate, creatine phosphate, and ATP will be obtained from biopsies of the ischemic region and microsphere determined blood flow will assess the uniformity of blood flow depletion. Groups of dogs biopsied at various time intervals after initiation of retrograde bleeding will assess for the persistence of metabolic gradients. This method will be applied to chronic dogs in which histological and CPK quantitation of transmural necrosis will be performed. The transmural progression of infarction with time in regions subjected to various intervals of uniform blood flow depletion and subsequent reperfusion will be compared to the traditional "wavefront" phenomenon. Recent evidence suggests that intramyocardial pressures during diastole are of significant magnitude and can influence the transmural distribution of blood flow. Preliminary work in our laboratory using coronary pressure-flow relationships obtained under constant pressure conditions have indicated that diastolic intramyocardial pressures are lower than previously reported. The difference in results is due to coronary capacitance. The quantitation of the diastolic intramyocardial pressures will be continued using pressure-flow relationships under constant pressure conditions. In addition, the capacitive properties of the coronary system will be fully characterized using the same experimental preparation. The transmural distribution of diastolic intramyocardial pressures will be assessed by pressure and regional microsphere blood flow relationships in a potassium arrested diastolic heart.